Blinatumomab in B-Cell Acute Lymphoblastic Leukemia with Positive Minimal Residual Disease: Initial Results of a Phase II Trial

Background: Chemoimmunotherapy offers excellent response rates for acute lymphoblastic leukemia (ALL). Persistence of minimal residual disease (MRD), delayed MRD negativity, and recurrence of MRD positivity portend higher risk of relapse and worse survival. Blinatumomab is a CD19/CD3 bispecific T-cell engager antibody construct which simultaneously engages CD3+ cytotoxic T cells and CD19+ ALL blasts enabling T-cell recognition and elimination of these leukemic cells. The BLAST study (Goekbuget, et al. Blood 2014;124:379) suggested the potential role of blinatumomab in eradicating MRD in precursor B-ALL. We aimed to evaluate blinatumomab in patients with pre-B ALL and positive MRD by multicolor flow cytometry and in patients with Philadelphia chromosome-positive (Ph+) ALL with positive MRD defined by polymerase chain reaction (PCR).

Methods: This was an open-label, single-arm, phase II trial. Pts with B-lineage ALL in hematologic complete remission (CR) who had either not achieved MRD negativity or had MRD-positive relapse, starting any time after ≥3 months (mo) of frontline therapy, or in CR2 and beyond at any time point after 1 mo of salvage therapy, and pts with prior allogeneic stem-cell transplantation (ASCT) were eligible for inclusion. MRD was defined as ≥1 x10^-4 by 6-color multiparameter flow cytometry. MRD for Ph+ ALL pts was defined as BCR-ABL1 to ABL1 transcripts of ≥0.1% International Scale by Real-Time qRT-PCR. Pts received continuous IV infusion of blinatumomab 28 µg/day over 4 weeks (wk) followed by 2 wk treatment-free interval. For the first cycle (cy), blinatumomab was initiated at 9 µg/day for 1 wk and then escalated to 28 µg/day, if tolerated. A TKI of treating physician's choice was added to the regimen for pts with Ph+ ALL. Responders could receive up to 4 additional consolidation cy, and subsequent ASCT was offered depending on donor availability. The primary endpoint was to evaluate the efficacy of blinatumomab in this population in terms of relapse free survival (RFS). Secondary endpoints were MRD negativity rate overall and after cy 1, overall survival (OS), and event-free survival.

Results: Between 12/2015 and 05/2017 we enrolled 12 pts with precursor-B ALL in CR. 3 pts (25%) had Philadelphia-like ALL and 2 pts (17%) had Ph+ ALL. Baseline characteristics are shown in Table 1. 9 pts (75%) were in CR1. Pts received a median of 2 cy (range, 1-4) of blinatumomab. 9 pts (75%) achieved MRD-negative status at a median time of 41 days (range, 38-92), and 3 pts did not achieve a response after 2 cy. 8 pts (67%) responded after first cy and 1 pt (8%) responded after second cy. 5 pts (42%) who responded, proceeded to ASCT with median time from enrollment to ASCT being 12.6 wk (range, 8.4-27.3). 5 pts (33%) have discontinued therapy, and 1 pt (8%) with response is currently receiving therapy on trial. Reasons for discontinuation were lack of response in 3 pts, toxicity in 1 pt (grade 3 psychosis and grade 2 encephalopathy), and loss of response in 1 pt. Out of the 3 pts who discontinued therapy due to lack of response, 1 pt underwent ASCT in MRD-positive CR, 1 pt is receiving blinatumomab outside of the clinical trial with vincristine and prednisone, and 1 pt is being evaluated for ASCT and is currently in MRD-positive CR. 1 pt who discontinued due to loss of response, underwent ASCT in morphologic relapse with 6% bone marrow blasts. Therapy was well tolerated and 8 pts (67%) have not had any adverse events. Toxicities encountered include grade 2 cytokine release syndrome in 2 pts, grade 1/2 peripheral neuropathy in 1 pt, and grade 3 psychosis and grade 2 encephalopathy in 1 pt. With a median follow-up of 8 mo (range, 2.3-19.1), 10 pts (83%) are alive. Out of the 2 pts who died, 1 pt did not respond to blinatumomab and died on day +25 post-ASCT from disseminated adenovirus infection, and 1 pt who had responded to blinatumomab but discontinued due to toxicity, died from sepsis in the setting of ALL relapse after ASCT. MRD negativity rates overall and after cy 1 were 75% and 67%, respectively. The 6 mo OS and RFS were 89% and 88%, respectively (fig. 1). The median OS and RFS have not been reached.

Conclusion: Blinatumomab is well-tolerated and is highly effective in eradicating MRD in pts with B-lineage ALL who have persistent MRD after intensive chemotherapy.

Clinical trial registration information: NCT02458014

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